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HIV/Aids Vaccines


 

 

Why an HIV/AIDS Vaccine is important

How do Vaccines work?

Types of Vaccines

Stages in developing a vaccine

Ethical and social issues involved in HIV vaccine development

Challenges in developing an HIV/AIDS vaccine

International efforts to develop an HIV vaccine

The South African AIDS Vaccine Initiative (SAAVI)

Developing an HIV vaccine in South Africa

Future Challenges

Contacts and websites


Why an HIV/AIDS Vaccine is important

Vaccines have saved millions of lives since the first modern one was developed in 1796. They are used today to prevent diseases such as chicken pox, smallpox, measles and mumps, to name a few. Naturally occurring smallpox and polio have virtually been eradicated due to global vaccination programmes.

It is important to note that a vaccine is not a cure – it is something that is given to prevent infection or disease.

The term vaccine, is generally used to describe medicinal products administered to individuals that provoke an immune response in order to teach the body to recognize a particular disease-causing organism in the future.

In this way the body is prepared to launch an effective attack against the particular organism, thereby preventing disease.

HIV/AIDS is one such organism that has impacted dramatically on people across the world.

There are currently approximately 4.5 million South Africans living with HIV/AIDS. The sub-Saharan region has the highest number of infections – of an estimated global total of 42 million, the sub-Saharan region is estimated to have over 29 million infected adults and children, according to the UNAIDS 2002 report.

It is for this reason that the development of an effective vaccine to protect people from infection is a high priority.

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How do Vaccines work?

The immune system is a complex collection of organs that produce cells that are used to fight diseases. These cells are called lymphocytes. Lymphocytes can be classed into 2 categories i.e. B-cells, which are produced in bone marrow, and T-cells, produced in the thymus. These cells are responsible for the body’s 2 primary immune responses, namely humoral (antibody) and cellular response.

Micro-organisms that invade the body have special protein markers that are recognized by the lymphocytes. These markers are called epitopes and they stimulate the release and replication of B and T cells. Certain types of T-cells can become ‘killer’ T-cells that attack and destroy infected cells. These cells are also called cytotoxic T cells or CTLs (cytotoxic lymphocytes).

T-cells are responsible for cellular immune response, since they engulf infected cells. T-cells are also responsible for regulating the overall immune response.

B-cells produce antibodies that circulate freely in the blood stream that destroys viruses floating freely in the blood by attaching themselves to the invading organisms thus preventing them from performing their function and targeting them for destruction. In this way, B-cells are responsible for humoral immunity, so named because they involve antibodies that are released in the blood and lymph systems.

After an attack, some B-cells remain in the blood to serve as memory B-cells that will mount a rapid response should the invader re-appear. This is the principle behind vaccines. The purpose of a vaccine is to stimulate the B and T cells into action so that memory cells are formed to prepare the immune system for future attacks by a particular disease. The immune system therefore learns how to fight back and keeps this memory in case it comes into contact with the same virus in future.

In addition to preventative vaccines, scientists are also currently trying to develop “therapeutic vaccines” for HIV. A therapeutic vaccine, aims to treat those who are already infected by delaying or slowing down disease progression and therefore the onset of AIDS. Both preventative and therapeutic vaccines for HIV are still in the very early stages of development.

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Types of Vaccines

Over the years, different types of vaccines have been developed to fight different diseases. Scientists have different approaches to developing vaccines. The traditional vaccines and the new or second-generation vaccines.

Traditional vaccines include:

  • Inactivated vaccines are produced by killing the disease-causing micro-organism with heat or chemicals, thus making it stable. These types of vaccines produce a relatively weak immune response and must be given more than once. e.g. cholera and flu vaccine. The flu vaccine is given every year also because the flu virus has many different strains.
  • Live-attenuated vaccines are grown in a lab to make the disease-causing agent lose its virulence (the disease-causing ability of a micro-organism). This type of vaccine needs special handling and storage in order to maintain its potency, but it only needs to be administered once. However, there is a possibility that the live organism may mutate and thus become virulent again. Examples of live-attenuated vaccines are yellow fever, measles and rubella vaccines.
  • A toxoid is an inactivated toxin (the harmful substance produced by a microbe). Many organisms that infect people are not in themselves harmful. It is the toxins they produce that cause disease. Scientists have manufactured vaccines that completely stop the production of these toxins in the body. Toxoids are used in tetanus and diptheria vaccines.

New and second-generation vaccines are the product of new technology that scientists have used to improve on traditional vaccines. New techniques, such as recombinant genetic engineering (or recombinant DNA technology) are being employed. This technique makes use of DNA from different sources that have been combined by the techniques of genetic engineering rather than by breeding experiments.

  • Conjugate vaccines. The organisms that cause some diseases like pneumococcal pneumonia have special outer coats that disguises it so that an immature immune system, like that of an infant, cannot recognise them. Conjugate vaccines use special proteins that the immature immune system can recognize and attach them to the organism. These vaccines are used to prevent meningitis.
  • Recombinant subunit vaccines – are produced by taking a part of the disease-causing microbe rather than the whole to create a synthetic antigen that will be able to produce an immune response. Most HIV candidate vaccines to date have been subunit vaccines.
  • Recombinant vector vaccines – are produced by using a virus or bacteria (not HIV) as a vector (carrier) for HIV genetic material. These carriers deliver the modified microbe to the part of the body that will produce the desired immune response.

Vaccines have saved millions of lives since the first modern one was developed in 1796. They are used today to prevent diseases such as chicken pox, smallpox, measles and mumps, to name a few. Naturally occurring smallpox and polio have virtually been eradicated due to global vaccination programmes.

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Stages in developing a vaccine

Vaccine development is a long process that will take many years – other vaccines have taken a number of decades to move from laboratory testing to general use. Vaccines are developed through a rigorous process of experiments that are based on thorough research and that are designed to answer specific scientific questions. The development process requires a concerted effort on the part of a variety of public sectors including scientists, companies, government, research institutions and communities.

The first stage involves Idea generation and research. Scientists start with a strategy for development based on knowledge and thorough research of HIV/AIDS, how it progresses and how it affects the body. It also involves ideas about what type of vaccine is needed and how the vaccine should function.

The second stage involves Pre-clinical development. The products that are selected to be used in a potential vaccine are tested in cell-cultures (a population of micro-organisms grown in a solid or liquid laboratory medium). If rigorous tests provide promising results, the potential vaccine is tested in small animals and non-human primates in a laboratory setting.

The third stage involves Clinical trials. If a potential vaccine is found to be safe in animals it is subjected to human testing. A clinical trial is a research study used to assess the benefits and risks of a new vaccine or treatment.

Human testing consists of 3 phases:

  • Phase I Trial. Measures mainly the safety, and side effects as well as early immune response (immunogenicity) of various doses of the test vaccine in a small number (usually 60 or less) of HIV-negative, low-risk, adult volunteers. It usually lasts for 12-18 months.
  • Phase II Trial. These are controlled trials that collect data on the safety, side effects and efficacy (it’s ability to prevent infection) of the vaccine as well as dosage and routes of administration. This phase usually involves between 200 and 500 HIV negative, adult, volunteers and can last up to 2 years.
  • Phase III Trial. This is a larger controlled trial to determine the effectiveness of the vaccine as well as the optimal dosage and schedule of the vaccine. It involves thousands of HIV-negative, usually high-risk volunteers and usually lasts for 3 to 4 years.

All three phases usually use placebo and control groups for comparison. (A placebo is a harmless, non-active substance that is designed to look like the test product.)

After the clinical trials have been completed and results are analysed, the vaccine may be licenced for use in the population. An application is made to the government department responsible for regulating pharmaceutical products for commercial use.

Once a vaccine is in general use - its efficacy, as well as optimal doses, safety aspects and adverse events are continually monitored – this is sometimes referred to as phase IV. A vaccine or drug can be withdrawn if it is found to have adverse effects in general use.

The next stage of vaccine development is delivery. Once a safe and effective vaccine has been developed, the challenge is to ensure that it is produced and delivered to those who need it- this means making provision for storage facilities and ensuring that delivery and application, even in remote rural areas, is optimal. Timeous delivery of an HIV vaccine is key to stemming the tide of infection.

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Ethical and social issues involved in HIV vaccine development

There are ethical principles that govern all research involving human subjects. Existing texts such as the Declaration of Helsinki, which was first adopted by the World Medical Association in 1964 and subsequently amended, are used as guidelines in clinical research. The UNAIDS code of ethics specifically deals with international vaccine trials.

There are currently a few key ethical concerns involved in the HIV vaccine development.These are:

  • Participants should give ongoing informed consent at all stages of the research process and should feel free to withdraw at any stage.
  • Participants must have a clear understanding of all the risks and responsibilities involved in participating in a trial.
  • Participants should have access to proven preventative methods such as condoms, treatment for other STD’s and ongoing risk-reduction counselling.
  • All participants (including those in the placebo group) should have access to the vaccine after the trials are completed.

HAVEG, which is funded by SAAVI, is researching ethical issues and developing country specific ethic guidelines as needed. The monitoring of AIDS vaccine trials in South Africa is done by the MCC, Data Safety and Monitoring Boards and Institutional Ethics Committees.

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Challenges in developing an HIV/AIDS vaccine

Vaccines have generally been developed to protect the individual against one strain of virus. HIV, however has the ability to mutate, thereby resulting in different strains. It is not yet known if it will be necessary to develop a vaccine against each subtype of HIV or if it will be possible to develop one that will protect against different subtypes. An ideal vaccine would protect against all HIV strains.

HIV vaccine development is complicated by the fact that HIV infects the very cells that a vaccine activates to produce immunity, namely the T-helper cells.The relationship between HIV and how it affects the immune system is still not completely understood. In order to develop a vaccine, scientists must first know which responses protect against which virus so that the vaccine can stimulate a specific response Researchers are studying why some individuals remain uninfected despite multiple exposure to the virus or why others remain asymptomatic for a long period of time after infection Challenges in developing an HIV/AIDS vaccine Vaccines have generally been developed to protect the individual against one strain of virus.

HIV, however has the ability to mutate, thereby resulting in different strains. It is not yet known if it will be necessary to develop a vaccine against each subtype of HIV or if it will be possible to develop one that will protect against different subtypes. An ideal vaccine would protect against all HIV strains.HIV vaccine development is complicated by the fact that HIV infects the very cells that a vaccine activates to produce immunity, namely the T-helper cells.

The relationship between HIV and how it affects the immune system is still not completely understood. In order to develop a vaccine, scientists must first know which responses protect against which virus so that the vaccine can stimulate a specific response Researchers are studying why some individuals remain uninfected despite multiple exposure to the virus or why others remain asymptomatic for a long period of time after infection.

The results of these studies would determine the natural protective state upon which a vaccine could be modelled.Because HIV can exist in the body as a free virus or infected cells, a vaccine will have to induce a response in both humoral (anti-body) and cellular immune response mechanisms – this has not been achieved yet with any of the test vaccines that have been developed.

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International efforts to develop an HIV vaccine

The International AIDS Vaccine Initiative (IAVI) is a global organization aimed at accelerating the development and distribution of preventive AIDS vaccines. IAVI’s work focuses on: mobilizing support through advocacy and education; accelerating scientific progress; encouraging industrial participation in AIDS vaccine development; and assuring global access. IAVI’s scientific effort is focusing on viral strains prevalent in developing countries and has enlisted developing country scientists as full partners.

European Vaccine Effort Against HIV/AIDS (EUROVAC) is funded by the European Union and includes twenty-one laboratories from France, Italy, Germany, the Netherlands, Spain, Sweden, Switzerland and United Kingdom participating in a cluster to bring European preventive HIV vaccines into Phase I clinical trials. The cluster is composed of three linked projects; EuroVac I, EuroVac II, and EuroVac III.

The International Council of AIDS Service Organizations (ICASO) is a non-governmental organization accredited to the United Nations Economic and Social Council (ECOSOC). It consists of a global network of non-governmental and community-based organizations and was formed in 1991 with secretariats in five geographic regions, and a central secretariat based in Canada.

The National Institutes of Health (NIH) is based in the United States and forms part of the U.S. Department of Health and Human Services. A component of the NIH is the HIV Vaccine Trial Network. This network comprises an international collaboration of scientists and institutions whose goal is to accelerate the search for an HIV vaccine by sharing trial results and facilitating parallel, concurrent testing.

Merck & Co. Inc. is a global research-driven pharmaceutical company that discovers, develops, manufactures and markets a broad range health products. Merck conducts research at 11 major research centers in the United States, Europe, and Japan, manufactures products in 32 facilities and sells products in approximately 150 countries.

Aventis Pasteur is a pharmaceutical company that exclusively concentrates its research on vaccines (cancer vaccine, STD information, AIDS, travel vaccinations, polio disease…).

Vaxgen Inc. is focused on the commercial development of biologic products for the prevention of and treatment of human infectious disease. Vaxgen split from Genentech in 1995 and is funded by the National Institutes of Health (NIH). VaxGen has two preventive AIDS vaccine candidates in Phase III clinical trials.

A full listing of HIV/AIDS vaccines currently being researched is accessible from the IAVI website.

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The South African AIDS Vaccine Initiative (SAAVI)

SAAVI is a national body that was established in 1999, by the South African cabinet and Eskom to co-ordinate the research, development and testing of an HIV/AIDS vaccine for South Africa.

SAAVI is based at the Medical Research Council (MRC) of South Africa in Cape Town and is headed by Dr. Tim Tucker. SAAVI contributes to international research with its focus on HIV-1 subtype C which is the most prevalent subtype in Southern Africa accounting for over 90% of new infections.

Local vaccine development will be based mainly on this strain of HIV, however, the aim is to develop a vaccine that will work in this region and if testing vaccines developed for other subtypes will provide useful scientific information for this goal then this will be done – but only if scientifically valid.

The overall goal of SAAVI is to produce a safe, effective, affordable and accessible HIV/AIDS vaccine for South Africa and the SADC region in as short a time as possible. Other interests include: advocacy and education, ethics and capacity building.

The primary funding for this initiative is received from Eskom and from the Departments of Health, and of Science and Technology (DST). Additional funding is received from other organisations like the US National Institutes of Health (NIH); the HIV Vaccine Trials Network (HVTN), the European Union and others. The initial funding from government was an amount of R5 million per year. This was doubled to R10 million per year in 2002.

The board of Eskom initially agreed to an annual payment of R7.5 million. However, in 2002 this amount was increased to R15 million.In addition, Eskom has agreed to contribute R15 million p.a. to the initiative until 2007 (is this per annum?){this info was taken from the SAAVI website which states R15 mil p.a}. To date Eskom has contributed more than R37 million to SAAVI – making it the largest corporate contribution to vaccine research in the world.

SAAVI has partnerships with several institutions. These include: the National Institute of Communicable Diseases (NICD), the Universities of Cape Town and Stellenbosch, the HIV/AIDS Vaccine Ethics Group (HAVEG) at the University of Natal, the Chris Hani Baragwanath Perinatal HIV/AIDS Research Unit, the MRC Vaccine Trials Unit, the Cape Town Clinical Trials Consortium, Aurum Health, and the South African HIV Vaccine Action Campaign (SA HIVAC).

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Developing an HIV vaccine in South Africa

Other groups in South Africa are working to develop a vaccine for HIV/AIDS. The Universities of Cape Town and Stellenbosch are noteworthy.

The University of Cape Town (UCT) Project

  • This team is researching vaccines using env and gag-pol genes from a local HIV-1 subtype C isolate.
  • Recombinant BCG (Bacillus Calmett-Guerin) and virus-like particles (VLP’s) produced in plants. These will be modified with the HIV proteins to be injected so that the body can produce a response without the risk of infection.
  • UCT has also worked with a biotech company Alphavax in the United States to produce a South African-based vaccine using the Venezuelan equine encephalitis virus (VEE) as a vector or carrier of a portion of the HI virus to produce an immune response.
  • The UCT team also received an award from the US National Institutes of Health (NIH) to fund the production of DNA vaccines developed by the SAAVI/University of Cape Town research group and an agreement with Cobra Therapeutics in the UK to manufacture and supply clinical trial and potentially commercial supplies of these vaccines – the manufacture of these initial vaccines is nearing completion.
  • The aim of the UCT team is to select the best strategy to progress to a Phase I trial in the near future.

The University of Stellebosch Project

  • The Department of Virology at the University of Stellenbosch is part of a team that is exploring more than one method of vaccine creation.
  • Some of their approaches include employing fungi called Aspergillus as a delivery system to express proteins, which could be used to form a subunit vaccine. This fungus is able to produce higher quantities of proteins.
  • The group is also collaborating with the Chiron Corporation in California exploring another concept. This concept uses microparticles that is bound to DNA and then injected as a DNA vaccine.

The traditional method of injecting a weakened form of the virus to produce an immune response will not be used for developing an HIV vaccine.

There are two reasons for this. Firstly, HIV mutates very quickly and there may be a danger of the weakened or attenuated virus becoming virulent. Secondly, because the HI virus integrates with the host cell, there may be a possibility that even a weakened form of the virus might integrate, exposing the individual to infection.

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Future Challenges

Some future challenges include.

  • Vaccines normally take a number of decades to produce and even if candidate vaccines proceed smoothly through the human testing phase it takes at least 7-10 years to complete all three phases. This is a long term process and a challenge is to maintain public interest and commitment to the process.
  • Investing in manufacturing and the development of safe and effective distribution mechanisms. SAAVI is currently collaborating with several organisations to ensure that the task of manufacturing and distributing a vaccine is taken into account.
  • It is likely that the first vaccines developed will not be 100% effective and in fact no vaccine is 100% effective. In the future a decision may have to be made about which level of efficacy would be acceptable for a vaccine to be considered effective at a public health level. Even if a successful vaccine was found tomorrow people would still need to practice safer sex.
  • Vaccines are the only long term solution to controlling a viral epidemic.

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Contacts and websites

SAAVI PIs

Michelle Galloway (SAAVI communications)
Tel: +27 (0) 21 938 0205
e-mail: michelle.galloway@mrc.ac.za

Online resources

International AIDS Vaccine Initiative, www.iavi.org

South African AIDS Vaccine Initiative, www.saavi.org.za

International AIDS Economics Network (IEAN),
http://www.iaen.org/vaccine/library.php

The National Institute of Allergy and Infectious Diseases. Division of AIDS,

HIV/AIDS Vaccines, http://www.niaid.nih.gov/daids/vaccine/default.htm

The Body, http://www.thebody.com/treat/vaccines.html

MRC AIDS Portal, www.afroaidsinfo.org.za

Online Publications

Arn, T. (2001). Vaccine Update. In: Being Alive, October 2001.
http://www.beingalivela.org/news1001/vaccine_update_1001.html

Ezzell, C. (2002). Hope in a Vial: Will there be an AIDS vaccine anytime
soon? Scientific American.com.
http://www.sciam.com/article.cfm?articleID=00055C5E-E3B5-1CDA-B4A8809EC588EE

England, S. (2000) PUSHING AND PULLING HIV/AIDS VACCINES Author(s): ;
International AIDS Vaccine Initiative (IAVI),
http://www.iaen.org/files.cgi/91_england.pdf

Forsythe, S. (2002) POTENTIAL BARRIERS TO DEMAND FOR AN AIDS/HIV VACCINE IN DEVELOPING COUNTRIES, International AIDS Economics Network, http://www.iaen.org/files.cgi/100_forsythe.pdf

Hepp News. (2001). HIV 101: HIV Vaccine Candidates. HIV Education Prison
Project, Volume 4, Issue 10. http://www.thebody.com/hepp/oct01/hiv101.html

Mirken, B. (2001). AIDS Vaccines: The Ethical and Social Issues. Bulletin of
Experimental Treatments for AIDS, San Francisco AIDS Foundation,
http://www.thebody.com/sfaf/summer01/vaccines.html

UNAIDS. (2000). Ethical considerations in HIV preventive vaccine research
UNAIDS guidance document. Prepublication version.
http://www.iaen.org/vaccine/library.php

UNAIDS. (2001). A Media Handbook for HIV Vaccine Trials in Africa. UNAIDS.
www.unaids.org

References

www.afroaidsinfo.org

www.saavi.org.za

www.niaid.nih.gov/factsheets/challvacc.htm

www.iaiv.org

Understanding Vaccinces; U.S Department of Health and Human Services; National Institute of Allergy and Infectious Diseases publication No. 98-4219, January 1998

Developing Vaccines to prevent HIV and AIDS – An Introduction for Community Group, International Council of AIDS Service Organizatons (ICASO), July 2000

The Science of HIV/AIDS vaccines: and introduction for community groups, International Council of AIDS Service Organizations (ICASO), 2003

Designing HIV-1 subtype C vaccines for South Africa, C. Williamson, L. Morris, E. Rybicki and A-L Williamson, South African Journal of Science 96, June 2000

MRC News, Vol 31, No.3, May 2000

THERE IS ALSO A HUGE AMOUNT OF COVERAGE/ADDITIONAL READING IN MY AIDS BULLETIN – SPECIFICALLY THE SAAVI ISSUE – VOL 11, NO. 2 JULY 2002





 
 

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